scholarly journals Devastating Metabolic Consequences of a Life of Plenty: Focus on the Dyslipidemia of Overnutrition

2013 ◽  
Vol 36 (5) ◽  
pp. 242 ◽  
Author(s):  
Gary F Lewis
Keyword(s):  
Insulin Resistance ◽  
Specific Aspect ◽  
Whole Body ◽  
Net Energy ◽  
Fat Storage ◽  
Integrative Physiology ◽  
Insulin Resistant ◽  
Health And Disease ◽  
Hormonal Action ◽  
Fat Depot

Although undernutrition and starvation continue to affect a substantial portion of the world’s population, billions of people in both developed and developing countries are affected by the opposite problem: consumption of calories that exceed their daily energy expenditure, a condition of overnutrition. The body’s response to a positive net energy balance is to store energy, predominantly as triglyceride molecules, in the subcutaneous and visceral fat compartments that expand and ultimately manifest in obesity. The body’s fat depot, however, does not have an infinite capacity to store and expand, and at set points, which differ from individual to individual and are also influenced by ethnicity, energy substrates ‘spill over’, resulting in ‘ectopic’ fat storage in tissues and organs that are not typically major fat storage depots in lean individuals. A complex web of nutrient overload, chronic inflammation, hormonal action, mitochondrial dysfunction and insulin resistance, to mention some of the factors involved, results in devastating metabolic abnormalities that have far reaching implications for health and disease, leading ultimately to some of the most common chronic diseases of our time; i.e., diabetes mellitus, cancer, chronic liver disease and atherosclerosis. Given the complexity and wide-ranging manifestations of overnutrition (also referred to here as insulin resistant states), we will highlight a specific aspect of the condition, that of dyslipidemia. This review will draw mainly on knowledge acquired from whole body, integrative physiology research in animals and humans affected by overnutrition, and will demonstrate how these types of studies can shed light on our understanding of the pathophysiology of the typical dyslipidemia of obesity, insulin resistance and type 2 diabetes.

scholarly journals Hepatokine ERAP1 impairs skeletal muscle insulin sensitivity via ADRB2/PKA pathway

2020 ◽  
Author(s):  
Feifan Guo ◽  
Yuguo Niu ◽  
Haizhou Jiang ◽  
Hanrui Yin ◽  
Fenfen Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Neutralizing Antibodies ◽  
Leptin Receptor ◽  
Whole Body ◽  
C2c12 Myotubes ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Sensitivity ◽  
Pka Pathway

Abstract The current study aimed to investigate the role of endoplasmic reticulum aminopeptidase 1 (ERAP1), a novel hepatokine, in whole-body glucose metabolism. Here, we found that hepatic ERAP1 levels were increased in insulin-resistant leptin-receptor-mutated (db/db) and high-fat diet (HFD)-fed mice. Consistently, hepatic ERAP1 overexpression attenuated skeletal muscle (SM) insulin sensitivity, whereas knockdown ameliorated SM insulin resistance. Furthermore, serum and hepatic ERAP1 levels were positively correlated, and recombinant mouse ERAP1 or conditioned medium with high ERAP1 content (CM-ERAP1) attenuated insulin signaling in C2C12 myotubes, and CM-ERAP1 or HFD-induced insulin resistance was blocked by ERAP1 neutralizing antibodies. Mechanistically, ERAP1 reduced ADRB2 expression and interrupted ADRB2-dependent signaling in C2C12 myotubes. Finally, ERAP1 inhibition via global knockout or the inhibitor thimerosal improved insulin sensitivity. Together, ERAP1 is a hepatokine that impairs SM and whole-body insulin sensitivity, and its inhibition might provide a therapeutic strategy for diabetes, particularly for those with SM insulin resistance.

scholarly journals Insulin Resistance in Osteoarthritis: Similar Mechanisms to Type 2 Diabetes Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Elena V Tchetina ◽  
Galina A Markova ◽  
Eugeniya P Sharapova
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
The Body ◽  
Whole Body ◽  
Insulin Resistant ◽  
Resistant State ◽  
Insulin Resistant State

Osteoarthritis (OA) and type 2 diabetes mellitus (T2D) are two of the most widespread chronic diseases. OA and T2D have common epidemiologic traits, are considered heterogenic multifactorial pathologies that develop through the interaction of genetic and environmental factors, and have common risk factors. In addition, both of these diseases often manifest in a single patient. Despite differences in clinical manifestations, both diseases are characterized by disturbances in cellular metabolism and by an insulin-resistant state primarily associated with the production and utilization of energy. However, currently, the primary cause of OA development and progression is not clear. In addition, although OA is manifested as a joint disease, evidence has accumulated that it affects the whole body. As pathological insulin resistance is viewed as a driving force of T2D development, now, we present evidence that the molecular and cellular metabolic disturbances associated with OA are linked to an insulin-resistant state similar to T2D. Moreover, the alterations in cellular energy requirements associated with insulin resistance could affect many metabolic changes in the body that eventually result in pathology and could serve as a unified mechanism that also functions in many metabolic diseases. However, these issues have not been comprehensively described. Therefore, here, we discuss the basic molecular mechanisms underlying the pathological processes associated with the development of insulin resistance; the major inducers, regulators, and metabolic consequences of insulin resistance; and instruments for controlling insulin resistance as a new approach to therapy.

Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity

2004 ◽  
Vol 287 (4) ◽  
pp. E799-E803 ◽  
Author(s):  
Gina B. Di Gregorio ◽  
Rickard Westergren ◽  
Sven Enerback ◽  
Tong Lu ◽  
Philip A. Kern
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Whole Body ◽  
Forkhead Transcription Factor ◽  
Intravenous Glucose ◽  
Insulin Resistant ◽  
Diet Induced Obesity ◽  
Tnf Α

FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test ( r = −0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA ( P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-α, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.

Introduction to the Kinases in Diabetes Biochemical Society focused meeting: are protein kinases good targets for antidiabetic drugs?

2005 ◽  
Vol 33 (2) ◽  
pp. 339-342 ◽  
Author(s):  
M.P. Coghlan ◽  
D.M. Smith
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Activity ◽  
Whole Body ◽  
Protein Kinase Activity ◽  
Pharmacological Agents ◽  
Insulin Resistant ◽  
Insulin Mimetic ◽  
Glucose Homoeostasis

Insulin regulates whole-body glucose homoeostasis by modulating the activities of protein kinases in its target tissues: muscle, liver and fat. Defects in insulin's ability to modulate protein kinase activity lead to ‘insulin resistance’ or impaired insulin action. Insulin resistance in combination with defective insulin secretion from the pancreas results in the elevated blood glucose levels that are characteristic of diabetes mellitus. Pharmacological agents that selectively modulate protein kinase activities in insulin-resistant tissues may act either as insulin-sensitizing or insulin-mimetic drugs. Consistent with this, small molecule modulators of a number of protein kinases have demonstrated efficacy in animal models of insulin resistance and diabetes. Moreover, emerging data in humans suggest that marketed anti-diabetic agents may also act in part through modulating protein kinase activities. This meeting was convened to consider the potential to treat insulin resistance and Type II diabetes by modulating protein kinase activity.

scholarly journals Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes

2020 ◽  
Author(s):  
Oana P. Zaharia ◽  
Klaus Strassburger ◽  
Birgit Knebel ◽  
Yuliya Kupriyanova ◽  
Yanislava Karusheva ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Lipid Content ◽  
Whole Body ◽  
Hepatic Lipid ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Glucose Tolerant ◽  
Hepatic Lipid Content

<a><b>Objective</b></a>: The rs738409(G) single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (<i>PNPLA3</i>) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently-described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (HCL) and insulin sensitivity in recent-onset diabetes mellitus. <p><b>Research Design and Methods</b>: A total of 917 participants of the German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution and magnetic resonance spectroscopy. </p> <p><b>Results:</b> The G allele associated positively with HCL (β=0.36, p<0.01), independent of age, sex and BMI across the whole cohort, but not in the individual clusters. SIRD exhibited lowest whole-body insulin sensitivity compared to severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the rs738409(G) SNP compared to other clusters and the glucose-tolerant control group (p<0.05). HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%, p<0.05], MARD [3.0 (1.0;7.9)%, p<0.001], SAID [0.4 (0.0;1.5)%, p<0.001] and the glucose tolerant group [0.9 (0.4;4.9)%, p<0.001]. Although the <i>PNPLA3</i> polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G allele carriers had higher circulating free fatty acid concentrations and greater adipose-tissue insulin resistance compared to non-carriers (both p<0.001).</p> <b>Conclusions:</b> Members of the severe insulin resistant diabetes cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose-tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.

scholarly journals Metabolically-Unhealthy Obesity Is Associated With Increased Adipose Tissue Inflammatory Gene Expression and 24-Hour Plasma Concentrations of PAI-1, but Not Other Inflammatory Cytokines

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A21-A22
Author(s):  
Max C Petersen ◽  
Gordon I Smith ◽  
Mihoko Yoshino ◽  
Vincenza Cifarelli ◽  
Jun Yoshino ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Plasma Concentrations ◽  
Fat Free Mass ◽  
Whole Body ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Markers Of Inflammation ◽  
Metabolically Healthy ◽  
Metabolically Unhealthy Obesity ◽  
Pai 1

Abstract Insulin resistant glucose metabolism is the most common metabolic complication associated with obesity; however, a subset of people with obesity have normal insulin sensitivity and are considered to be metabolically healthy. In rodent models of obesity, adipose tissue (AT) inflammation contributes to whole-body insulin resistance mediated, at least in part, by production of proinflammatory cytokines that are secreted into the systemic circulation. We therefore hypothesized that AT markers of inflammation and plasma concentrations of inflammatory cytokines would be greater in people with metabolically-unhealthy obesity (MUO) and insulin-resistant glucose metabolism than in insulin-sensitive people with metabolically-healthy obesity (MHO). We measured AT expression of genes that encode for proinflammatory proteins by using RNA sequencing and plasma cytokine concentrations assessed serially over 24 hours by using multiplex assays in: i) 28 people with MHO (defined as normal glucose tolerance and normal insulin-stimulated glucose disposal assessed using the hyperinsulinemic-euglycemic clamp procedure [48 ± 2 µmol/kg fat-free mass/min]); and ii) 28 people with MUO (defined as prediabetes and impaired insulin-stimulated glucose disposal [28 ± 1 µmol/kg fat-free mass/min]). AT markers of inflammation (expression of SERPINE1, CCL3, CCL5, CD68, CD74, MRC1, and CXCL16) were greater in the MUO than in the MHO group (all P &lt; 0.05). However, the 24-hour plasma concentration areas-under-the curve (AUC) for TNFα, MCP-1, IL-6, RANTES, IL-1β, IL-17, and IFN-γ were not different between MHO and MUO groups. In contrast, 24-hour plasma plasminogen activator inhibitor 1 (PAI-1) AUC was greater in the MUO (1,759 ± 169 ng/mL x h) group than in the MHO (716 ± 85 ng/mL x h) group (P &lt; 0.001) and plasma PAI-1 was inversely correlated with whole-body insulin sensitivity (r= -0.57; P &lt; 0.001). We conclude that, with the exception of PAI-1, AT inflammation does not contribute to whole-body insulin resistance by increasing systemic circulating inflammatory cytokine levels. However, increased AT production of PAI-1 is associated with whole-body insulin resistance in people with MUO.

Abstract 17025: Myeloid Rage Protects From Insulin Resistance in Mice Fed High Fat Diet

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Lakshmi Arivazhagan ◽  
Henry Ruiz ◽  
Robin Wilson ◽  
Laura Frye ◽  
Ravichandran Ramasamy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Body Mass ◽  
High Fat Diet ◽  
Whole Body ◽  
High Fat ◽  
Double Knockout ◽  
Euglycemic Clamp ◽  
Insulin Resistant ◽  
Hyperinsulinemic Euglycemic Clamp

Introduction: Obesity is a major global health problem, with over one third of adults in the US classified as obese. Obesity often leads to a state of insulin resistance (IR), type 2 diabetes (T2D) and its complications. We previously showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and IR, as whole body and adipocyte-specific Ager (gene encoding RAGE) deleted mice fed a high fat diet (HFD) were significantly protected from weight gain and IR. Here, we hypothesize that myeloid RAGE contributed to IR upon HFD feeding. Methods: We generated mice with myeloid-specific (MDR) LyzMCre(+/+).Ager flox/flox and adipocyte and myeloid-specific (Double Knockouts) AdipoQCre(-/+)LyzMCre(+/+).Ager flox/flox deletion of Ager and LysMCre mice were used as control. Mice were fed either standard chow (LFD) or HFD (60% kcal/fat) for 3 months starting at age 6 weeks. Mice were assessed for body mass and composition, glucose and insulin sensitivity and whole body glucose metabolism by hyperinsulinemic-euglycemic clamp studies. Results: After 3 months HFD, there were no significant differences in body mass, body composition, food intake, energy expenditure and physical activity of the MDR mice vs. controls. Similar findings were observed in mice fed LFD. However, surprisingly, in HFD-fed mice, insulin tolerance tests and hyperinsulinemic-euglycemic clamp studies showed decreased insulin sensitivity and insulin action in the MDR vs. control mice, indicating that the MDR mice were more insulin resistant. The Double Knockout (myeloid/adipocyte) Cre (+) mice were more glucose tolerant and insulin sensitive compared to MDR mice, showing that deletion of Ager in the adipocytes rescued the adverse effects of Ager deletion in myeloid cells. Conclusions: Myeloid Ager protects from IR in mice fed HFD. Furthermore, in MDR mice, concomitant adipocyte-specific deletion of Ager rescues these mice from IR and, at the same time, reduces HFD-induced adiposity. The mechanisms underlying these findings are under active investigation.

Abstract 629: Niacin Beneficially Alters the Secretion of Intestinal HDL in a Rat Model of Insulin Resistance by Opposing Effects on PPAR Alpha and TNF Alpha

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Rabban Mangat ◽  
Faye Borthwick ◽  
Tina Ullrich ◽  
Miriam Jacome ◽  
Donna F Vine ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Composition ◽  
Whole Body ◽  
Tnf Alpha ◽  
Cvd Risk ◽  
Ppar Alpha ◽  
Insulin Resistant ◽  
Mesenteric Lymph ◽  
Opposing Effects ◽  
Hdl Metabolism

INTRODUCTION: Niacin is the oldest hypolipidemic drug that effectively lowers plasma triglycerides whilst increasing HDL-C concentration. However the mechanism of action of niacin still remains elusive. Emerging evidence shows that in addition to the liver, the intestine also contributes to whole body HDL metabolism. The effect of insulin resistance and niacin on intestinal HDL secretion is unclear. OBJECTIVE: To determine the effect of niacin on the secretion and composition of intestinal lymphatic HDL in a model of insulin resistance (JCR:LA-cp rat). METHODS: Insulin resistant (IR) rats were fed control chow or chow supplemented with niacin (1% w/w) for 6 weeks. The mesenteric lymph duct was cannulated and lymph sampled following an intra-gastric intralipid (fed) infusion for 6 hrs. The lymphatic HDL (1.063-1.21g/ml) fraction was separated by density ultracentrifugation; associated lipid and protein composition was analyzed. Primary enterocytes were isolated by an adaptation of the Wieser method. Jejunal explants from IR rats were treated with 5mg/ml niacin or nicotinamide and mRNA expression was assessed. RESULTS: In IR rats, apo-AI lymphatic HDL secretion was reduced (-47%), but associated TG content enriched (86%), compared to non-IR rats. Interestingly, niacin was found to stimulate the secretion of lymph HDL (>60%) compared to non-treated IR rats. Niacin treatment also normalized the TG content of lymphatic HDL particles. In parallel experiments, niacin was also shown to beneficially reduce lymphatic apoB secretion, suggesting concomitant pathways. Primary enterocytes isolated from niacin treated animals had increased ABCA1 and PPAR alpha mRNA compared to untreated control. Further, niacin (but not nicotinamide) significantly increased PPAR alpha and CPT1a mRNA, while annulling TNF alpha mRNA in treated jejunal explants. Conversely, there was no effect of niacin or nicotinamide treatment on ATGL, PLIN2 or ATG5. CONCLUSION: Insulin resistance may reduce the secretion of apoAI HDL into mesenteric lymph, potentially contributing to particle dysfunction. Niacin may contribute to improving CVD risk by restoring the number and TG enrichment of intestinal apoAI particles.

scholarly journals Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

1997 ◽  
Vol 273 (5) ◽  
pp. E859-E867 ◽  
Author(s):  
M. Hettiarachchi ◽  
S. Chalkley ◽  
S. M. Furler ◽  
Y.-S. Choong ◽  
M. Heller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthesis ◽  
Human Growth ◽  
Whole Body ◽  
Nonesterified Fatty Acids ◽  
Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

scholarly journals Skeletal Muscle Insulin Resistance in Endocrine Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Melpomeni Peppa ◽  
Chrysi Koliaki ◽  
Panagiotis Nikolopoulos ◽  
Sotirios A. Raptis
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Polycystic Ovary ◽  
Glycogen Synthesis ◽  
Whole Body ◽  
Endocrine Disorders ◽  
Peripheral Tissues ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance

We summarize the existing literature data concerning the involvement of skeletal muscle (SM) in whole body glucose homeostasis and the contribution of SM insulin resistance (IR) to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS), adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.

Sign in / Sign up

Export Citation Format

Share Document